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The interaction of high-fat diet and the peptide YY (PYY) gene expression in diet-induced obesity and the mechanisms which predisposed some individuals to become obese on high-fat diet were explored. Thirty-six male SD rats were randomly divided into high-fat diet group (n=27) and chow fed control group (n=9). After 15 weeks of either a high-fat diet or chew fed diet, the high-fat diet group was subdivided into dietary induced obesity (DIO) and dietary induced obesity resistant (DIR) group according to the final body weight. Then the DIO rats were subdivided into two groups for a 8-week secondary intervention. One of the group was switched to chew fed diet, whereas the other DIO and DIR rats continued on the initial high-fat diet. Weight gain and food intake were measured, food efficiency was calculated, and the concentrations of plasma neuropeptide Y (NPY) and PYY were assayed. Hypothalamic NPY mRNA expression and PYY mRNA expression in ileum and colon was detected by RT-PCR. The results showed that at the end of 15th week, the levels of body weight and caloric intake were significantly higher in DIO group than in DIR or control group (P<0.01), while no significant difference was found between DIR and control group (P>0.05). The concentration of plasma PYY was significantly higher in DIR group than in DIO and CF group, while no significant difference was found between DIO and CF group (P<0.01). After switching the DIO rats to chow fed diet, their body weight gains were significantly lower than that of the DIO-HF group. The expression of PYY mRNA was increased in DIO-HF/CF rats than in DIO-HF rats, and the expression of hypothalamic NPY mRNA was decreased in DIO-HF/CF rats than in DIO-HF group. It was concluded that both dietary composition and PYY gene expression could potently alter the hypothalamic NPY expression and result in different susceptibility to obese and overeating. The decreased PYY was associated with the increased NPY expression and their predisposal to obese and overeating in rats.